ABSTRACT Alcohol use disorder (AUD) is a chronic and relapsing condition for which current pharmacological treatments are only modestly effective. The development of efficacious medications for AUD remains a high research priority with recent emphasis on identifying novel molecular targets for AUD treatment and to efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) has been advanced as a novel addiction pharmacotherapy that targets neurotrophin signaling and neuroimmune function. IBUD inhibits phosphodiesterases -4 (PDE4) and -10 (PDE10) and macrophage migration inhibitory factor. To advance medications development for AUD, our laboratory has recently completed a randomized, double-blind, placebo-controlled crossover laboratory study of IBUD in non-treatment seeking individuals with current AUD (R21 AA022214; NCT02025998). This study tested the safety, tolerability, and initial human laboratory efficacy of IBUD (50mg BID). Results indicated that IBUD was well tolerated and associated with mood improvements during stress- and alcohol-cue exposures as well as reductions in tonic levels of alcohol craving. Building upon the strong rationale and preclinical findings for IBUD, along with safety data and early efficacy in human testing conducted in our laboratory, this proposal seeks to conduct a 12-week, double-blind, placebo controlled randomized clinical trial of IBUD (50mg BID). We propose to randomize 132 treatment-seeking men and women with current AUD. The primary aims are (a) to test whether IBUD (50mg BID) will decrease percent heavy drinking days (PHDD; HDD defined as 5+ drinks for men and 4+ for women), as compared to placebo, over the course of the 12-week trial; and (b) to test the efficacy of IBUD (50mg BID) on secondary alcohol consumption endpoints, namely (a) drinks per day, (b) drinks per drinking day, (c) percent days abstinent, (d) percent subjects with no heavy drinking days, and (e) percent subjects abstinent, as well as measures of alcohol craving and negative mood, over the course of the 12-week trial. The successful completion of the proposed study will further develop IBUD, a safe and promising novel compound with strong preclinical and safety data for AUD. If IBUD proves superior to placebo in this study, it will set the stage for a confirmatory multi-site trial leading to FDA approval of a novel AUD treatment.